Bolstering Bowel And Bladder Control With Dignify Therapeutics' Karl Thor

In this episode of Sit and Deliver, host Tom von Gunden talks with Chief Scientific Officer Karl Thor of Dignify Therapeutics about providing relief for patients suffering from neurogenic bowel and bladder dysfunction. Karl outlines two routes of administration for control-gaining treatments: one, sublingual delivery of a peptide-based therapy; the other, a small molecule therapy delivered via suppository.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver, the series in which we hear about innovations in drug delivery from leading thinkers in the industry. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for this series. Today I am joined by Karl Thor, Chief Scientific Officer at Dignify Therapeutics, a company which is working on treatments for folks who suffer from challenges with bowel and bladder evacuation.

Welcome, Karl.

Karl Thor, Chief Scientific Officer, Dignify Therapeutics:

Thank you, Tom. It's a pleasure to be here.

Well, it's good to have you with us. So. let's start by talking about those patients out there. So, we know that you're working on treatments for addressing challenges with bowel and bladder evacuation. I think most of us can probably account for some personal experience on occasion. But I know that there are folks for whom this is more of a chronic condition. So, can you talk about that patient population that you're working on targeting?

Yes, that patient population is very severe. It's not just your [infrequent] constipation; it’s people with what's called neurogenic bowel and bladder dysfunction. And these are folks with neurological conditions such as spinal cord injury, multiple sclerosis, Parkinson's disease, and children with rare pediatric diseases, such as spina bifida.

So, when the connections between the brain and the spinal cord are damaged, the brain can no longer control the bowel and bladder. This is similar to when the brain loses control of the leg muscles in people with spinal injury, multiple sclerosis, neurological conditions. So, when the brain loses control of the bowel and bladder, they can no longer voluntarily start to defecate or urinate.

And they cannot prevent involuntary release of urine and feces, which is called fecal and urinary incontinence. As you can imagine, the fear of having a fecal incontinence accident at work or during social events greatly restricts their interactions. And many surveys have shown that people with these conditions considered restoring control of their bowel and bladder function to be more important than restoring control of their movements.

Wheelchairs are not convenient, but they are not as restrictive as suffering from a frequent incontinence episodes in regards to a social life. So those are the primary people. But we will have a halo effect in the general population that has constipation.

Thinking about the current state for those folks, what are their [treatment] options today, if any? How do people typically deal with this, if they deal with it at all, in advance of what you're working on that they may have in their possession down the road?

You have to urinate and defecate on a regular basis just to survive. So, to urinate, most people with these neurological conditions are required to insert a catheter through the urethra into the bladder five or six times a day in order to urinate. Or they will have a permanent catheter inserted through their abdomen into the bladder to collect the urine in a leg bag. These bladder catheters encourage urinary tract infections that require hospitalization, which is a major expense for our healthcare system.

To defecate, two-thirds of the people with spinal injury require what's called a manual bowel program. And this is a bit graphic, but it requires insertion of their fingers or their caregiver’s fingers into their butt and manual extraction of the stool.

And this process can take anywhere from 30 minutes to 2 hours in a significant portion of the population. They and most other people with neurogenic bowel also often require suppositories or enemas. Among the problems with these methods of inducing defecation is that they can take a long time to work, and when and where the defecation starts and stops are very unpredictable with enemas and suppositories. And so, this can produce later episodes of fecal incontinence.

And, after consulting with dozens of people with these neurological conditions, we became aware that the predictability of the start and stop of the drug’s effect was even more important than the drug's reduction in the time required to empty the bowel. So that will be one of our primary data points that we want to capture is, how predictable is our drug in producing these effects?

Thanks for the detail there. I know that you're working on a couple of different treatments or therapies: one delivered orally — sublingually, as I understand it; the other via suppository. So, let's talk about them in order. Let's talk first about the orally delivered treatment. I believe it's peptide-based at its core. So, tell us what you can about the formulation, the mechanism of action, what it's attempting to do, how quickly, and what the benefit is.

So, we have two problems with swallowing a peptide pill. The first is that peptides are destroyed by the stomach acids. And the second is that we need a very rapid and consistent time for absorption and elimination of the drug, as I told you, and that's not practical with intestinal absorption.

So, there can be great variability in how quickly the drug is absorbed and how long it stays in your body. So, we plan to start our clinical proof of concept with an intramuscular injection because it provides a very consistent and rapid delivery of our peptide, and it could have valuable clinical application for relief of post-operative constipation and urinary retention after surgery.

So, obviously this is not practical for daily use in people with neurogenic bowel dysfunctions. So, we're developing a sublingual. We examined sublingual and intranasal absorption in animal studies, and both routes provided rapid and consistent effects. But to produce equivalent effects, the sublingual route required about 20-fold higher amounts of the drug than the intranasal dose.

Now, there are also problems with the intranasal delivery, in that a device to provide an accurate dose is expensive. And if the person has nasal congestion, the absorption of a drug could be delayed and not consistent. So, therefore, we considered the use of a sublingual film. And we knew that we would require higher doses when we did our animal studies with the film because we know that anesthesia reduces salivation, which is needed to dissolve the film.

And we knew that the sublingual absorption of drops in humans is more efficient from the sublingual mucosa than our lab animals. And finally, the film we tried first was really just an off-the-shelf, more or less generic film that our vendor was kind enough to infiltrate with our peptide for free to examine feasibility.

And we believe that we can reduce the amount of drug 5- to 10-fold over our animal studies. And we just submitted an application to the NIH to fund a project to optimize that film specifically for the delivery of our peptide. So, that's where we are with that sublingual formulation.

Let's move on then and talk about the suppository-oriented delivery. Tell us a little bit about what you're formulating and developing there. And also, maybe help us understand the choices and the scenarios for the patients, where they might benefit from one versus the other, after we hear about the second.

So, our suppository contains a different drug. It's not a peptide. It's a small molecule, and it's designed to work locally on the internal surface of the rectum to stimulate sensory receptors that will trigger a reflex contraction through the nervous system and cause the colon to contract and the sphincter to relax, which promotes defecation.

[By contrast] our sublingual peptide produces a contraction of the colon and bladder by directly stimulating the muscles, and it makes the bladder and colon contract and push the stool and urine out. So, these are two very different mechanisms. And we expect that there may be individuals in which the efficacy and the tolerability are different, because their bowel dysfunction can be caused by different mechanisms.

Also, the side effect profile: Since our peptide works directly on the GI tract, someone who has a sensitive GI tract may notice some side effects that they wouldn't notice if they use the suppository. And similarly, we anticipate there are going to be some side effects from the suppository. But since the drug is really absorbed into the systemic system, you wouldn't have to worry about drug-drug interactions or anything like that because it's just working locally.

So, we have two different mechanisms. And we're going to have to really go into the clinic and see if they're equally efficacious, and look at the side effect profiles, and look at the different populations. For example, the location of a spinal cord injury could be different. The degree a person with Parkinson's disease might have different control than the person with spinal cord injury.

So, it's a brand-new field. There are no drug companies actually going after this rapid onset, short duration physiologically resembling defecation.

Gotcha. And so, is there anything that you're looking at or thinking about, in terms of other patient needs and other therapeutic areas, that some of these formulations or mechanisms of action might be effective in once you get outside the work that you're doing on the bowel and bladder issues?

So, our current focus is getting the bound bladder to excrete. But the other problem for these folks, as I mentioned in the introduction, is their urinary and fecal incontinence. So, we have two NIH-funded projects for treating — one for urinary, one for fecal incontinence that uses proprietary parenteral formulations. And we have one unfunded project for treating overactive bladder that we would use the sublingual film formulation.

And just one final question for you, Karl. As you look out to the horizon and beyond in terms of the health and lives of patients, assuming that the treatments that you're working on are successful and effective, how do you see the lives and health of those patients once these things are [accessible]?

We hope to eliminate or reduce the use of bladder catheters and manual bowel programs. And we hope that by providing a convenient means of regularly emptying the bowl and bladder we can also eliminate or reduce fecal and urinary incontinence episodes and the need for adult absorbent products.

So, based on our conversations, again, with dozens of people suffering from neurological bowel and bladder disorders, achieving our goals would make an immediate and very impactful improvement in the professional and social quality of life for these patients. It would allow them to operate in public without the fear of embarrassing themselves and being in a stigmatizing situation.

That's great. All sounds very promising, very reassuring. I want to thank you, Karl, for joining me and sharing with our audience your perspectives and the work that's going on there at Dignify Therapeutics. And to our audience, I want to thank you again for joining us for another episode of Sit and Deliver. See you next time.